Pathological investigations of tissue from multiple sclerosis (MS) and Guillain-Barre syndrome (GBS) patients have shown macrophages containing myeline debris in and around demyelinating lesions. In MS, GBS, and experimental inflammatory demyelination in animals, demyelination appears only to occur in the presence of macrophages. Ultrastructural studies suggest that macrophages become closely apposed to the myelin sheath and remove myelin from the axon. Demyelination in animal models can be delayed or reduced by treatment with agents that impair macrophage function. It is not clear, however, to what extent macrophages begin the process of demyelination, extend demyelination initiated by other mechanisms, or act as scavengers of previously damaged myelin sheaths. This project is designed to establish the degree of involvement of macrophages in the initiation, execution, and termination of the demyelinating process. This will be accomplished by examination of the interaction of functionally different populations of macrophages with a range of well-defined myelin preparations consisting of isolated myelin components, reconstituted myelin vesicles, and in vitro myelinating cultures. The investigations will include: 1) binding of macrophages to myelin, both directly and via intermediate ligands; 2) study of the effect of the nervous system environment on macrophage function; 3) study of the ability of endogenous and exogenous macrophages to demyelinate in vitro myelinating culture systems; and 4) application of these findings to the study of macrophages from animals with experimental demyelinating diseases.